PROJECT SUMMARY/ABSTRACT Teresa K. Chen, MD, MHS is an Assistant Professor in the Division of Nephrology at Johns Hopkins University School of Medicine. She is applying for a K08 Mentored Clinical Scientist Research Career Development Award in order to acquire the necessary skills and mentored research experience to become an independent investigator in the field of chronic kidney disease (CKD). The proposed 5-year plan includes advanced coursework in epidemiology; practical experience in the measurement of biomarkers; and mentorship by an extraordinarily experienced, committed and diverse mentorship team [co-primary mentors, Lawrence Appel, MD, MPH and Morgan Grams, MD, PhD; co-mentor, Michelle Estrella, MD, MHS]. With resources provided by this award, Dr. Chen will develop proficiencies in study design, genetic and molecular epidemiology, and longitudinal data analysis related to CKD. Her proposed research project focuses on the role of immune activation in CKD progression and the interactive effects of immune activation with APOL1 risk variants. African Americans are disproportionately affected by CKD. This is in part due to the higher prevalence of APOL1 risk variants, genetic risk factors for kidney disease among individuals of African ancestry. The role of immune activation in the progression of non-diabetic CKD, particularly in APOL1 high-risk individuals, is unclear. The objectives of the proposed research are to: 1) study the associations of biomarkers of immune activation with CKD progression among non-diabetic African Americans with CKD attributed to hypertension; 2) determine whether the APOL1-associated risk for CKD progression is augmented by immune activation; 3) assess whether blood pressure interventions and dietary factors are associated with longitudinal changes in biomarkers of immune activation; 4) identify metabolomic predictors of biomarkers of immune activation. With over 10 years of follow-up, rigorously collected data, and stored biospecimens, the African American Study of Kidney Disease and Hypertension (AASK) represents an ideal cohort in which to study these potential associations. APOL1 genotyping and metabolomics measurements have previously been completed in AASK through other NIH-funded mechanisms. We propose to use stored serum samples from the baseline and 12- month visits of the trial phase to measure the following biomarkers of immune activation: tumor necrosis factor alpha (TNF-?), soluble TNF receptors 1 and 2 (sTNFR1 and sTNFR2), and interferon gamma (IFN-?). The results of the proposed study will clarify the role of immune activation in CKD progression and perhaps identify novel targets for intervention. This could have important clinical implications in the treatment of African Americans with non-diabetic CKD, particularly among those with the APOL1 risk variants. The proposed research will also support Dr. Chen's long term-goal of transitioning towards an independent research career that ultimately improves the management and outcomes of African Americans with CKD. The rich training environment of Johns Hopkins University will ensure that she achieves these goals.